Novel method for lowering blood pressure in mammals

ABSTRACT

This disclosure describes a method of lowering blood pressure in mammals by the administration of compositions containing as the active component certain 6-(substituted-phenyl)-5-methyl-4,5dihydro-3(2H)-pyridazinones.

United States Patent 1191 Curran NOVEL METHOD FOR LOWERING BLOODPRESSURE IN MAMMALS [75] Inventor: William Vincent Curran, Pearl 21Appl. No.: 259,704

Related US. Application Data [63] Continuation-impart of Ser. No.l5l,l55, June 8,

197 l abandoned.

[52] US. Cl. 424/250 [51] Int. Cl A6ll 27/00 [58] Field of Search424/250 [11] 3,812,256 May 21, 1974 [56] References Cited UNITED STATESPATENTS 3,475,431 10/1969 Bachmann et a1. 260/250 PrimaryExaminer-Jerome D. Goldberg Attorney, Agent, or Firm-EdwardA. Conroy,Jr.

[ 5 7 ABSTRACT This disclosure describes a method of lowering blood 0pressure in mammals by the administration of compositions containing asthe active component certain 6-(substituted-phenyl)-5-methyl-4,5-dihydro-3(2H)- pyridazinones.

4 Claims, No Drawings PRESSURE IN MAMMALS CROSS REFERENCE TO RELATEDAPPLICATION This application is a continuation-in-part of my copendingapplication Ser. No. 151,155, filed June 8, 1971, now abandoned.

BRIEF SUMMARY OF THE INVENTION This invention relates to newcompositions of matter for lowering blood pressure. More particularly,it relates to therapeutic compositions containing certain 6-(substituted-phenyl)--methyl-4,5-dihydro-3(2H)- pyridazinones whichoperate to reduce blood pressure in mammals. The invention includes thenew compositions of matter and methods of lowering blood pressuretherewith.

The invention is based uponthe discovery that certain6-(substituted-phenyl)-5-methyl-4,5 dihydro- 3(2H)-pyridazinones arepotent hypotensive agents. The 6-( substituted-phenyl)-5-methyl-4,5-dihydro- 3( 2H )-pyridazinones of the present inventionmay be represented by the following general formula:

wherein R is hydrogen or methyl and R is nitro, amino, or loweralkanoylamino. Suitable lower alkanoylamino groups contemplated by thepresent invention are those having up to four carbon atoms such asformylamino, acetylamino, propionylamino, nbutyrylamino andisobutyrylamino. The novel compounds of the present invention wherein Ris amino are organic bases and thus are capable of forming acidadditionsalts with a variety of non-toxic organic and inorganic salt-formingreagents. Thus, acid-addition salts, formed by admixture of the organicfree base with an acid, suitably in a neutral solvent, are formed withsuch acids as sulfuric, phosphoric, hydrochloric, hydrobromic, sulfamic,citric, lactic, malic, succinic, tartaric, acetic, benzoic, gluconic,ascorbic, and related acids. For purposes of this invention these freebases are equivalent to their non-toxic acid-addition salts.

DETAILED DESCRIPTION OF THE INVENTION The6-(substituted-phenyl)-5-methyl-4,5-dihydro- 3(2l-l)-pyridazinones ofthe present invention may be administered either orally or parenterally.The amount of a single dose or of a daily dose to be given will vary butshould be such as to give a proportionate dosage of from about 1 mg. toabout mg. per kilogram of body weight per day. Thus, such dosage unitsare employed that a total of from about 50 mg. to about 1.0 g. for asubject of about 70 kg. body weight are administered in a 24 hourperiod. This dosage regimen maybe adjusted to provide the optimumtherapeutic response, for example, several doses of 25-250 mg. may beadministered daily or the'dose may be proportionately re- NOVEL METHODFOR LOWERING BLOOD gelatin capsules, or they may be compressed intotablets, or they may be incorporated directly with the food of the diet.For oral therapeutic administration, the active compounds of thisinvention may be incorporated with excipients and used in the form oftablets, troches, capsules, elixirs, suspensions, syrups, wafers, andthe like. Such compositions and preparations should contain at least 0.1percent of active compound. The percentage in the composition andpreparations may, of course, be varied and may conveniently be betweenabout 5 percent to about percent or more of the weight of the unit. Theamount of active compound in such therapeutically useful compositions orprepara tions is such that a suitable dosage will be obtained. Preferredcompositionsor preparations according to the present invention areprepared so that an oral dosage unit form contains between about 25 and250 milligrams of active compound.

The tablets, troches, pills, capsules and the like may also contain thefollowing: a binder such as gum tragacanth, acacia, corn starchorgelatin; an excipient such as dicalcium phosphate; a disintegratingagent such as corn starch, potato starch, alginic: acid and the like; alubricant such as magnesium stearate; and a sweetening agent such assucrose, lactose, or saccha'rin may be added or a flavoring agent suchas peppermint, oil of Wintergreen, or cherry flavoring. When the dosageunit form is a capsule, it may contain in addition to materials of theabove type a liquid carrier such as a fatty oil. Various other materialsmay be present as coatings or to otherwise modify the physical form ofthe dosage unit, for instance, tablets, pills or capsules may be coatedwith shellac, sugar, or both. A syrup or elixir may contain the activecompounds, sucrose as a sweetening agent, methyl and propyl parabens aspreservatives, a dye and a flavoring such as cherry or orange flavor. Ofcourse, any material used in preparing any dosage unit form should bepharmaceutically pure and substantially non-toxic in the amountsemployed.

Compositions having the desired clarity, stability, and adaptability forparenteral use are obtained by dissolving from 0.10 percentto 10.0percent by weight of a6-(substituted-phenyl)-5-methyl-4,5-dihydro-3(2H)- pyridazinone in avehicle consisting of a mixture of non-volatile, normally liquidpolyethylene glycols which are soluble in both water and organic liquidsand which have molecular weights of from about 200 to about 1,500. Suchmixtures of polyethylene glycols are commercially available and areusually obtained by condensing glycol with ethylene oxide. Although theamount of 6-(substituted-phenyl)-5-methyl-4,5-dihydro-3(2H)-pyridazinonedissolved in the above vehicle may vary from 0.10 percent to 10.0percent by weight, it is preferred that the amount employed be fromabout 3.0 percent to about 9.0 percent by weight. Although variousmixtures of the aforementioned nonvolatile polyethylene glycols may beemployed, it is preferred to use a mixture of non-volatile polyethyleneglycols having an average molecular weight of about 400. Such a mixtureis usually referred to as polyethylene glycol 400. A preferredembodiment comprises a clear solution of from about 3.0 percent to about9.0 percent by weight of the 6-(substituted-phenyl)-5-methyl-4,5-dihydro-3(2l-l)-pyridazinone dissolved in an aqueous solution ofpolyethylene glycol 400. In addition to theG-(Substituted-phenyl)--methyl-4,5-dihydro-3(2H)- pyridazinone, theparenteral solutions may also contain various preservatives which may beused to prevent bacterial and fungal contamination or chemicaldegradation.

The novel compounds of the present invention possess an asymmetriccarbon atom at the 5-position and hence may exist in more than onestereoisomeric form. It is to be understood that the present inventionincludes within its scope all such stereoisomeric forms.

The following examples illustrate the preparation and hypotensive effectof the novel compositions of the present invention and the method ofadministering them.

EXAMPLE 1 Preparation of -(m-nitrophenyl)-5-methyl-4,5-dihydro-3(2H)-pyridazinone 3-Benzoylbutyric acid [Lutz et al.,J.A.C.S. 75, 5039 (1953)] was dissolved in 20 ml. of conc. nitric acid,cooled, and 20 ml. of conc. sulfuric acid was added over 30 min. withstirring. The mixture was then stirred at room temperature for 1.5hours, and then poured onto ice. The resulting gum was extracted withchloroform which was washed with saturated salt solution, then dried (MgSO Evaporation of the chloroform gave an amber oil which resistedcrystallization.

The above oil was'refluxed for one hour in 20 ml. of ethanol containing1.0 ml. of hydrazine hydrate, treated with Norit, and filtered. Thefiltrate deposited crystals of 6-(m-nitrophenyl)-5-methyl-4,5-dihydro-3(2H)-pyridazinone; m.p. l89-l92 C. The product was recrystallized fromethanol to afford light yellow crystals; m.p. l9ll94 C.

EXAMPLE 2 Preparation of 6-(m-aminophenyl)-5-methyl- 4,5-dihydro-3 2H)-pyridazinone A mixture of 1.2 g. of 6-(m-nitrophenyD-imethyl-4,5-dihydro-3(2H)-pyridazinone, 0.25 g. of 10 percent palladium oncarbon, ml. of ethanol, and 10 ml. of cyclohexene was refluxed for 18hours, filtered, and evaporated to give an oil which crystallized.Recrystallization from ethyl acetate-hexane, followed by ethanol,afforded the 6-(m-aminophenyl)-5-methyl-4,5- dihydro-3(2H)-pyridazinone;m.p. l43l45 C.

EXAMPLE 3 Preparation of 6-(m-formamidophenyl)-5-methyl-4,5-dihydro-3(2H)-pyridazinone A mixture of 10 g. of6-(m-aminophenyl)-5-methyl- 4,5-dihydro-3(2H)-pyridazinone in 100 ml. oftoluene containing 10 ml. of formic acid is refluxed for one hour whileremoving water azeotropically in a Dean- Stark trap. Evaporation of thesolvent in vacuo affords the -(m-formamidophenyl)-5-methyl-4,5-dihydro-3(2H)-pyridazinone.

EXAMPLE 4 Preparation of 6-(m-acetamidophenyl )-5- methyl-4,5-dihydro-3(2H )-pyridazinone A mixture of 0.25 g. of -(m-aminophenyU-S-methyl-4,5-dihydro-3(2H)-pyridazinone in 1.0 ml. of acetic anhydride washeated on a steam bath for 5 minutes. White crystals of the6-(m-acetamidophenyl)-5- methyl-4,5-dihydro-3(2H)-pyridazinone, m.p.2l6219 C., were obtained upon cooling and filtration.

EXAMPLE 5 Preparation of 6-(m-propionamidophenyl)-5-methyl-4,5-dihydro-3(2H)-pyridazinone By replacing the acetic anhydrideemployed in Example 4 with an equimolecular quantity of propionicanhydride and following substantially the same procedure described inExample 4, there is obtained the6-(mpropionamidophenyl)-5-methyl-4,5-dihydro-3(2H)- pyridazinone.

EXAMPLE 6 Preparation of 6-[m-(n-butyr'amido)phenyl]-5-methyl-4,5-dihydro-3(2H)-pyridazinone The procedure of Example 4 isrepeated, substituting 4 an equimolecular amount of n-butyric anhydridefor the acetic anhydride employed in that example. There is thusobtained the 6-[m-(n-butyramido)phenyl]-5-methyl-4,5-dihydro3(2H)-pyridazinone.

EXAMPLE 7 Preparation of 6-[m-(iso-butyramido)phenyl]-5-methyl-4,5-dihydro-3(2H)-pyridazinone In place of the acetic anhydrideof Example 4 there is employed an equimolecular quantity of isobutyricanhydride whereby the 6-[m-(iso-butyramido)phenyl]-5-methyl-4,5-dihydro-3(2l-l)-pyridazinone is obtained in equally goodyield.

EXAMPLE 8 Hypotensive activity of 6-(substituted-phenyl)-5-methyl-4,5-dihydro-3(2H)-pyridazinones in normotensive rats Conscious malealbino Sherman strain rats were fastened to rat boards in a supineposition by means of canvas vests and limb ties. The femoral areas wereanesthetized by subcutaneous infiltration of lidocaine. The left orright common iliac arteries were exposed and clamped off proximally byan artery clamp and distally with thread. lncisions were made near thetie and short nylon catheters were inserted and tied in place. The otherend of the catheters were fitted with 24 gauge hubless needles attachedto thick-walled polyethylene tubes. The o-(substituted-phenyl)-5-methyl-4,5-dihydro-3(2H)-pyridazinones were administered to the animals orallyby stomach tube. The compounds were suspended in 2 percent aqueousstarch solution, 1 ml. of which gave, per g. of body weight, the desireddose. Volume was usually 2.5 ml. since the rats average 250 g. inweight. Mean arterial blood pressure was measured 4 hours afteradministration of the compounds. Comparisons were then made to the meancontrol pressure of 121 1+: 7 mm. of mercury. Blood pressuremeasurements were made with four Statham P23 Db strain gauges attachedto a Sanborn Polyviso Re I corder. The recorder is equipped with fourstrain gauge EXAMPLE lO-Continued Preparation of Oral Syrup Formulationingredient Amount Cherry flavor 50 mg. Distilled water, qs. ad I00 ml.

The sorbitol solution is added to 40 ml. of distilled water and theactive ingredient is suspended therein.

The sucaryl, saccharin, sodium benzoate, flavor and dye are added anddissolved in the above solution. The volume is adjusted to 100 ml. withdistilled water.

Other ingredients may replace those listed in the above formulation. Forexample, a suspending agent such as bentonite magma, tragacanth,carboxymethylcellulose or methylcellulose may be used. Phosphates,

citrates or tartrates may be added as buffers. Preservatives may includethe parabens, sorbic acid and the like and other flavors and dyes may beused in place of those listed above. 7

EXAMPLE ll Preparation of Parenteral Formulation In a solution of l 19ml. of propylene glycol and ml. of distilled waterwas dissolved 8.5 g.of 6-(maminophenyl)-5 methyl-4,5-dihydro-3(2H) pyridazinonehydrochloride, with stirring. After dissolution was complete, a solutionof 850 mg. of sodium formaldehyde sulfoxylate in 30ml. of distilledwater TABLE I Oral Dose Compound mg./kg. of No. of MBP body weight ratsmm. Hg

Controls 50 l2li7 6-(m-nitrophenyl)-5-methyl- 4,5-dihydro-3(2H)'Pyidazinone I00 3 79 6-(m-aminophenyU-S-methylt4,5-dihydro-3t2lU-pyridazinone 100 x 2 86 ti-(macetamidophenyU-S-methyl-4,5-dihydro-3t2H)- pyridazinone 100 2 82 6'(m-nitrophenyl)-2.5'dimethyl-4,5-dihydro-3(2H)- pyridazinone lOO 2 66 EXAMPLE 9 Preparationof Tablet Formulation Per For 10,000 Ingredient Tablet Tablets Activeingredient: -(m-nitro- V phenyl)-5-methyl-4,S-dihydro'3(2H)-pyridazinone 0.0500 500 Lactose 0.0800 800 Corn Starch (for mix)0.0l50 I50 Corn Starch (for paste) 0.0100 100 0.|550 L550 MagnesiumStearutc (1%) 0.00l3 l2.5

The active ingredient, lactose and corn starch (for mix) are blendedtogether. The corn starch (for paste) is suspended in 800 milliliters ofwater and heated with stirring, to form a paste. This paste is then usedto granulate the mixed powders. Additional water is used, if necessary.The wet granules are passed through a No. 8 hand screen and dried at 120F. The dry granules are then passed through a No. 16 screen. The mixtureis lubricated with 1 percent magnesium stearate and compressed intotablets in a suitable tableting machine.

dimethyl-4,5-dihydro-3(2H)-pyridazin0ne was then added to theformulation. The pH of this solution was then adjusted to 7.0withethanolamine and the volume was made up to. l ml. with distilled water.The formulation was filtered through a fine sintered glass filter,filled into 5.0 ml. ampoules each containing 2.0 ml., and sealed undernitrogen.

EXAMPLE 12 Preparation of 6-( m-formamidophenyl)-2,5-dimethyl-4,5-dihydro-3(2H)-pyridazinone A mixture of 10 g. of6-(m-aminophenyl)-2,5- dimethyl-4,5-dihydro-3(2H)-pyridazinone in ml. oftoluene containing 10 ml. of formic acid is refluxed for one hour whileremoving water azeotropically in a Dean-Stark trap. Evaporation of thesolvent in vacuo affords the 6-(m-formamidophenyl)-2,5-dimethyl-4,5-dihydro-3(2H)-pyridazinone.

EXAMPLE 13 Preparation of 6-(rn-acetamidophenyl)-2,5-dimethyl-4,5-dihydro-3(2H)-pyridazinone A mixture of 0.25 g. of6-(m-aminophenyl)-2,5- dimethyl'4,5-dihydro-3(2H)-pyridazinone in 1.0ml. of acetic anhydride is heated on a steam bath for 5 minutes. Whitecrystals of the 6-(m-acetamidophenyl)-2,5- are obtained upon cooling andfiltration.

EXAMPLE 14 Preparation of -(m-propionamidophenyl)-2,5-dimethyl-4,5-dihydro-3(2H)-pyridazinone By replacing the aceticanhydride employed in Example 13 with an equimolecular quantity ofpropionic anhydride and following substantially the same procedure isthus obtained the 6-[m-(n-butyramido)phenyl]-2,5- dimethyl-4,5-dihydro-32H )-pyridazinone.

EXAMPLE [7 Preparation of 6-(m-nitrophenyl)-2,5-dimethyl-4,5-dihydro-3(2H)-pyridazinone A solution of 4.47 g. of3-(m-nitrobenzoyl)butyric acid and 2.4 ml. of methylhydrazine in ml. ofethanol is heated at reflux temperature for 3 hours. The solution iscooled to give a solid which is recrystallized from dilute methanol tofurnish 3.23 g. of white crystals, m.p. 94-96 C.

EXAMPLE 18 Preparation of 6-(m-aminophenyl)-2,5-dimethyl-4,5-dihydro-3(2H)-pyridazinone A mixture of 2.56 g. of4,5-dihydro-2,5-dimethyl-6- (mnitrophenyl)-3(2H)-pyridazinone and 250mg. of 10 percent palladium-on-carbon in 50 ml. of ethanol is shakenunder hydrogen in a Parr apparatus until the pressure is constant (13minutes). The mixture is filtered and the filtrate is evaporated to givean oil that crystallizes from ether-petroleum ether to give 2.10 g. ofcrystals, m.p. l20-l22 C.

I claim:

1. A therapeutic composition in dosage unit form useful for loweringblood pressure in mammals comprising from about 50 mg. to about 1.0 gramper daily dosage unit of-(m-nitrophenyl)-5-methyl-4,5-dihydro-3(2H)-pyridazinone, and apharmaceutical carrier.

2. A therapeutic composition in dosage unit form useful for loweringblood pressure in mammals comprising from about 50 mg. to about 1.0 gramper daily dosage unit of 6-(m-nitrophenyl)-2,5-dimethyl-4,5-dihydro-3(2H)-pyridazinone, and a pharmaceutical carrier.

3. The method of lowering blood pressure in a mammal which comprisesadministering internally to said mammal an effective amount of6-(m-nitrophenyl)-5- methyl-4,5-dihydro-3(2H)-pyridazinone, inassociation with a pharmaceutical carrier to provide a daily dosage offrom about 1 mg. to about 15 mg. per kilogram of body weight of saidmammal. i

4. The method of lowering blood pressure in a mammal which comprisesadministering internally to said mammal an effective amount of6-(m-nitrophenyl)-2,5- dimethyl-4,5-dihydro-3(2H)-pyridazinone, inassociation with a pharmaceutical carrier to provide a daily dosage offrom about 1 mg. to about 15 mg. per kilogram of body weight of saidmammal.

2. A therapeutic composition in dosage unit form useful for loweringblood pressure in mammals comprising from about 50 mg. to about 1.0 gramper daily dosage unit of6-(m-nitrophenyl)-2,5-dimethyl-4,5-dihydro-3(2H)-pyridazinone, and apharmaceutical carrier.
 3. The method of lowering blood pressure in amammal which comprises administering internally to said mammal aneffective amount of6-(m-nitrophenyl)-5-methyl-4,5-dihydro-3(2H)-pyridazinone, inassociation with a pharmaceutical carrier to provide a daily dosage offrom about 1 mg. to about 15 mg. per kilogram of body weight of saidmammal.
 4. The method of lowering blood pressure in a mammal whichcomprises administering internally to said mammal an effective amount of6-(m-nitrophenyl)-2,5-dimethyl-4,5-dihydro-3(2H)-pyridazinone, inassociation with a pharmaceutical carrier to provide a daily dosage offrom about 1 mg. to about 15 mg. per kilogram of body weight of saidmammal.